LTA4 hydrolase inhibitors

ABSTRACT

The invention relates to compounds which constitute a class of medicaments which have an anti-inflammatory activity and which act by inhibiting leukotriene A 4  (LTA 4 ), and enzyme which is responsible for the biosynthesis of leukotriene LTB 4 , a major proinflammatory mediator. The invention also relates to therapeutic anti-inflammatory, applications of these compounds as well as for methods of preparing these compounds.

This application is a divisional of application Ser. No. 09/958,160filed Jan. 8, 2002 now U.S. Pat. No. 6,878,723, which is the NationalStage of International Application No. PCT/FR00/00876, filed Apr. 6,2000.

The present invention relates to compounds as defined hereinafter, whichconstitute a class of medicaments having mainly an anti-inflammatoryactivity and/or acting by inhibiting LTA₄ (leukotriene A₄) hydrolase, anenzyme which is responsible for the biosynthesis of leukotriene LTB₄, amajor proinflammatory mediator.

It also relates to such compounds useful in the form of prodrugs.

It also relates to methods for preparing these compounds.

LTA₄ hydrolase (EC 3.3.2.6.) is an enzyme which is in particular presentin the neutrophils and whose sequence has been recently shown (Funck etal., P.N.A.S., 1987, 89: 6677) to be related to that of a zincmetallopeptidase, aminopeptidase M (Malfroy et al., B.B.R.C., 1989, 161:236). In agreement with the suggestion by Malfroy et al., it has beenrecognized that LTA₄ hydrolase possesses a zinc atom which is essentialfor its catalytic activity, an aminopeptidase-type activity, and issensitive to the action of certain metallopeptidase inhibitors(Heggstrom et al., B.B.R.C., 1990, 173: 431; Minami et al., B.B.R.C.,1990, 173: 620).

The inhibition of LTA₄ hydrolase is capable of preventing the formationof LTB₄, a mediator responsible for the adhesion of the neutrophils tothe endothelial cells and for their chemotaxis. It appears to beinvolved in the etiology or the symptomatology of a variety ofconditions and inflammatory states such as rheumatoid arthritis, chronicinflammations of the intestine, multiple sclerosis, gout and psoriasis.In these processes, LTB₄ is thought to act in synergy with othermetabolites of arachidonic acid which are produced by 5-lipoxygenase orcyclooxygenases whose inhibition is well known to produceanti-inflammatory effects.

Some LTA₄ hydrolase inhibiting compounds have been described, inparticular in patent applications WO 94/00420, WO 96/11192, WO 96/10999and WO 96/27585, WO 96/41625, WO 98/40354, WO 98/40364, WO 98/40370, WO98/09943 and WO 98/43954.

The objective of the present invention is to provide novel compoundscapable of inhibiting LTA₄ hydrolase.

The objective of the present invention is also to provide compoundswhich can be used as medicaments.

To this end, the subject of the invention is the use of compounds offormula (I) as defined below as inhibitors of the activity of LTA₄hydrolase, in particular as anti-inflammatory agents.

The subject of the invention is also the use of these compounds offormula (I) in the form of prodrugs.

These compounds correspond to the following formula (I):

in which

-   -   X is selected from the following groups:        -   i) —NH₂

-   -   n₁ and n₃ are equal to 0 or 1, with (n₁+n₃) equal to 0 or 1    -   n₂ varies from 0 to 10    -   Y is selected from the following groups:        -   i) —O—        -   ii) —CH₂—        -   iii) —S—        -   iv) —NH—        -   v) —OCH₂—    -   R¹ is selected from the following groups:        -   i) a hydrogen atom        -   ii) a lower alkyl group        -   iii) a cycloalkyl group        -   iv) a phenyl group which is unsubstituted or which is mono-            or polysubstituted with substituents selected from halogen            atoms and CF₃, lower alkyl, lower alkoxy, NH₂, NO₂, CN, OH,            CO₂H, OPh, OCH₂Ph, SCH₃, SCH₂CH₃ and NHCOR⁶ groups        -   v) an α- or β-naphthyl group        -   vi) an anthracene group        -   vii) -A²-(CH₂)_(n4)-A¹ where            -   n₄ varies from 0 to 4            -   A¹ and A² are independently selected from the following                groups:            -   a) cycloalkyl            -   b) phenyl which is unsubstituted or which is mono- or                polysubstituted with substituents selected from halogen                atoms and CF₃, lower alkyl and lower alkoxy groups,            -   c) 2-, 3- or 4-pyridyl            -   d) 2- or 3-thienyl            -   e) 2- or 3-furyl            -   f) 2-, 3- or 4-piperidyl            -   g) cycloalkene        -   viii) a 2-, 3- or 4-pyridyl group        -   ix) a 2- or 3-thienyl group        -   x) a 2- or 3-furyl group

-   -   Z is selected from the following groups:        -   i) —COOR⁷

-   -   -   v) —SO₃H        -   vi) —SO₂NHR¹¹        -   vii) —CONHSO₂R¹¹

    -   R² and R³ are independently selected from the following groups:        -   i) a hydrogen atom        -   ii) a lower alkyl group        -   iii) a lower alkyl group substituted with a halogen atom        -   iv) a CF₃ group        -   v) a halogen atom        -   R⁴ and R⁵ are independently selected from a hydrogen atom or            a lower alkyl group, a phenyl group which is unsubstituted            or which is substituted with a halogen atom, a CF₃ group, a            lower alkyl group, a lower alkoxy group and an OH group.        -   n₅ varies from 0 to 2        -   R⁶ represents a lower alkyl group        -   R⁷ represents a hydrogen atom, a lower alkyl group, a group            —(CH₂)_(n6)-Ph, n₆ varying from 0 to 4 and Ph being a phenyl            group which is unsubstituted or which is mono- or            polysubstituted with a halogen atom, a CF₃ group, a lower            alkyl, a lower alkoxy or an OH group        -   R⁸ and R⁹ are independently selected from a hydrogen atom, a            phenyl group, a lower alkyl group and a lower            acetylthioalkylene group        -   R¹⁰ represents a lower alkyl group, a group —(CH₂)_(n7)-Ph,            n₇ varying from 1 to 6 and Ph being a phenyl group which is            unsubstituted or which is mono- or polysubstituted with a            halogen atom, a CF₃ group, a lower alkyl or a lower alkoxy        -   R¹¹ represents a lower alkyl group or a phenyl group.

The expression lower alkyl group is understood to mean an alkyl grouphaving a linear or branched chain containing from 1 to 10 carbon atoms,preferably 1 to 4 carbon atoms.

The expression lower alkoxy group is understood to mean an alkoxy groupcontaining a linear or branched chain having from 1 to 10 carbon atoms,preferably 1 to 4 carbon atoms.

The expression cycloalkyl group is understood to mean a ring containingfrom 5 to 7 carbon atoms, preferably 6 carbon atoms, such ascyclopentane, cyclohexane or cycloheptane.

The expression cycloalkene group is understood to mean a ring containingfrom 5 to 7 carbon atoms and containing a double bond, preferably 6carbon atoms, such as cyclohexene.

The expression lower acetylthioalkylene group is understood to mean anacetylthio group having a linear chain containing from 1 to 4 carbonatoms, preferably 1 to 2 carbon atoms.

The halogen atoms are preferably selected from chlorine and fluorine.

The invention also comprises the isomers of the compounds of formula(I), including the diastereoisomeric and enantiomeric forms.

The invention also extends to the therapeutically acceptable salts ofthese compounds, as well as to the salts of their isomers, including thediastereoisomeric and enantiomeric forms.

The expression therapeutically acceptable salts is understood to mean asalt which does not adversely affect either the chemical structure orthe pharmacological properties of the compounds of the presentinvention. Such salts include inorganic and organic anions such ashydrochloride, hydrobromide, acetate, trifluoroacetate, maleate,fumarate, oxalate and the like, which are well known in the art. Thesesalts are prepared in a conventional manner by neutralizing thecompounds of formula (I) with the desired acid.

The subject of the invention is also the compounds of formula (I) perse, with the exception:

-   (α) of the compounds in which Z is a group of the COOR⁷ type and    n₁=n₃=0 and R²=H and R¹ is a group iv) of the phenyl type which is    unsubstituted or which is mono- or polysubstituted, and in which    n₂=1, and-   (β) of the following compounds: α-amino-β-phenoxy-propionic acid,    3-amino-7-phenylheptanoic acid, 3-amino-6-phenoxyhexanoic acid,    α-amino-6-phenylhexanoic acid and α-amino-5-phenoxypentanoic acid.

The subject of the invention is also pharmaceutical compositionscomprising at least one such compound.

The inventors have demonstrated that the compounds of formula (I)defined above, or their salts obtained with therapeutically acceptableinorganic or organic acids or their stereoisomers, possess a potent LTA₄hydrolase inhibiting activity.

The compounds (I) exhibit, moreover, good bioavailability and haveproved to have low toxicity.

The present invention describes a series of compounds capable ofpotently inhibiting LTA₄ hydrolase.

These compounds exhibit, in addition, biological activity as indicatedhereinafter which confers therapeutic interest on them.

According to a first aspect of the invention, a preferred group ofcompounds of the abovementioned formula (I) comprises those for which Xrepresents NH₂ and/or Z represents the group —COOR⁷ with R⁷ representinga hydrogen atom.

In this group, the compounds of formula (I) in which X is NH₂ and Z isCOOH, are more particularly preferred.

The compounds of formula (I) in which R² and/or R³ represent a hydrogenatom also constitute a particularly preferred subgroup according to theinvention.

R² and R³ are preferably each a hydrogen atom.

The compounds of formula (I) with R² and/or R³ different from hydrogenrepresent another subgroup according to the invention.

A subfamily among the abovementioned compounds is formed by thecompounds for which n₁ and n₃ are equal to 0.

Another subfamily consists of the compounds for which n₁ or n₃ isdifferent from 0.

A subclass of compounds according to the invention also consists ofthose for which n₂=0. Among these compounds, Y preferably represents—O—.

Another subclass is formed by the compounds for which n₂ varies from 1to 5, preferably from 2 to 5 and in a more particularly preferred mannerfor the compounds where n₂=3.

Another class of compounds according to the invention is defined bythose where n₂ is greater than 5.

From the point of view of the symbol Y, the compounds for which thelatter represents an oxygen atom are particularly preferred according tothe invention.

Other subfamilies may be defined according to whether Y represents—CH₂—, a sulfur atom, a unit —NH— or —OCH₂—.

R¹ is preferably selected from a phenyl group which is unsubstituted orwhich is substituted, more preferably monosubstituted, with one of theabovementioned substituents.

When R¹ symbolizes a substituted phenyl group, the substituent(s) arepreferably selected from lower alkyl, lower alkoxy, OPh and OCH₂Phgroups.

The compounds for which R¹ is a phenyl group which is mono- orpolysubstituted with an OPh group constitute a preferred subfamilyaccording to the invention.

When R¹ represents a unit -A²-(CH₂)_(n4)-A¹, A² is more preferably aphenyl group which is preferably unsubstituted.

Among these compounds, n₄ is preferably equal to 0 or 1 and A¹ ispreferably selected from a phenol, cycloalkyl and cycloalkene group.

R¹ representing a unit -A²-(CH₂)_(n4)-A¹ is preferably a phenyl groupsubstituted with a Ph, CH₂Ph, CH₂-cycloalkyl or CH₂-cycloalkene group,more preferably a CH₂Ph or CH₂-cycloalkyl group.

Another subfamily comprises the compounds (I) for which R¹ represents ahydrogen atom or a lower alkyl group.

Another subfamily comprises the compounds (I) for which R¹ is acycloalkyl group.

The compounds (I) with R¹ representing an α- or β-naphthyl group, or ananthracene group also form another subfamily.

Another group of compounds according to the invention comprises thecompounds (I) with R¹ representing a 2-, 3- or 4-pyridyl, 2- or3-thienyl and 2- or 3-furyl group.

The compounds (I) with R¹ representing

also form another subgroup according to the invention.

For all the subfamilies mentioned above, the substituents not specifiedmay vary according to their respective general definitions.

A particularly preferred group of compounds according to the inventionconsists of the compounds corresponding to the following formula (II):

in which X, n₂, n₃, Y, R¹ and R⁷ have the above meaning.

The preferences previously indicated for the compounds of formula (I)also apply to those of formula (II).

A group which is even more particularly preferred comprises thecompounds corresponding to the following formula (III):

in which n₂, n₃, Y and R¹ have the meaning indicated above.

The particular choices mentioned for the compounds of formula (I) fromthe point of view of the symbols Y and R¹ also apply to the compounds offormula (III).

Among these compounds, those corresponding to the following formula(IV):

where Y, n₂ and n₃ have the meaning given above and Ar symbolizes thegroup R¹ representing phenol group iv) optionally substituted as definedabove or R¹ representing a group vii) -A²-(CH₂)_(n4)-A¹, A² being aphenyl group (b) optional substituted as defined above are particularlypreferred.

According to a second aspect of the invention, a preferred group ofcompounds of formula (I) which is mentioned above comprises those forwhich X represents NH₂ and/or Z represents the group

R⁸, R⁹ being a hydrogen atom, and R¹⁰ having the abovementioned meaning.

In this group, the compounds of formula (I) in which X is NH₂ and Z is

are more particularly preferred.

The compounds of formula (I) in which R² and/or R³ represent a hydrogenatom also constitute a particularly preferred subgroup according to theinvention.

R² and R³ are preferably each a hydrogen atom.

The compounds of formula (I) with R² and/or R³ different from hydrogenrepresent another subgroup according to the invention.

A subfamily among the abovementioned compounds is formed by thecompounds for which n₁ and n₃ are equal to 0.

Another subfamily consists of the compounds for which n₁ and/or n₃ aredifferent from 0.

A subclass of compounds according to the invention also consists ofthose for which n₁=0. Among these compounds, Y preferably represents—O—.

Another subclass is formed by the compounds for which n₂ varies from 1to 5, preferably from 2 to 5 and in a more particularly preferred mannerfor the compounds where n₂=3.

Another class of compounds according to the invention is defined bythose where n₂ is greater than 5.

From the point of view of the symbol Y, the compounds for which thelatter represents an oxygen atom are particularly preferred according tothe invention.

Other subfamilies may be defined according to whether Y represents—CH₂—, a sulfur atom, or a unit —NH— or —OCH₂—.

R¹ is preferably selected from a phenyl group which is unsubstituted orwhich is substituted, more preferably monosubstituted, with one of theabovementioned substituents.

When R¹ symbolizes a substituted phenyl group, the substituent(s) arepreferably selected from halogen atoms, CF₃, lower alkyl, lower alkoxy,NO₂, CN, NH₂, CO₂H, OPh, OCH₂Ph and NHCOR⁶ groups.

The compounds for which R¹ is a phenyl group which is mono- orpolysubstituted with halogen atoms or lower alkoxy groups constituteanother subfamily according to the invention.

When R¹ represents a unit -A²-(CH₂)_(n4)-A¹, A² is more preferably aphenyl group which is preferably unsubstituted.

Among these compounds, n₄ is preferably equal to 0 or 1 and A¹ ispreferably a phenyl group.

R¹ representing a unit -A²-(CH₂)_(n4)-A¹ is preferably a phenyl groupsubstituted with a Ph or CH₂Ph group, more preferably a CH₂Ph group.

Another subfamily comprises the compounds (I) for which R¹ represents ahydrogen atom or a lower alkyl group.

Another subfamily comprises the compounds (I) for which R¹ is acycloalkyl group.

The compounds (I) with R¹ representing an α- or β-naphthyl group, or ananthracene group also form another subfamily.

Another group of compounds according to the invention comprises thecompounds (I) with R¹ representing a 2-, 3- or 4-pyridyl, 2- or3-thienyl and 2- or 3-furyl group.

The compounds (I) with R¹ representing

also form another subgroup according to the invention.

For all the subfamilies mentioned above, the substituents not specifiedmay vary according to their respective general definitions.

A particularly preferred group of compounds according to the inventionconsists of the compounds corresponding to the following formula (V):

in which X, n₂, Y, R¹, R⁸ and R⁹ have the above meaning.

The preferences previously indicated for the compounds of formula (I)also apply to those of formula (V).

A group which is even more particularly preferred comprises thecompounds corresponding to the following formula (VI):

in which n₂, Y and R¹ have the meaning indicated above.

The particular choices mentioned for the compounds of formula (I) fromthe point of view of the symbols Y and R¹ also apply to the compounds offormula (VI).

Among these compounds, those corresponding to the following formula(VII):

where Y and n₂ are as defined above and Ar symbolizes R¹ representing aphenyl group iv) optionally substituted as defined above or R¹representing a group vii) -A²-(CH₂)_(n4)-A¹, A² being a phenyl group (b)optionally substituted as defined above, are particularly preferred.

Another group of compounds according to the second aspect of the presentinvention comprises the compounds corresponding to the following formula(VIII):

where X, Y, n₂, R¹, R⁸ and R¹⁰ have the above meaning.

The preferences indicated above for the compounds of formula (I) alsoapply to those of formula (VIII).

A third aspect of the invention relates more particularly to thecompounds of formula (I) where Z represents the group

A fourth aspect of the invention more particularly relates to thecompounds of formula (I) where Z represents an —SO₃H, —SO₂NHR¹¹ or—CONHSO₂R¹¹ group.

Among the compounds of the present invention, the following areparticularly preferred:

-   1) (S)-O-4-benzylphenoxyserine hydrochloride

-   2) 2-(RS)-amino-6-(4-benzylphenoxy)hexanoic acid hydrobromide

-   3) 2-(RS)-amino-5-(4-benzylphenoxy)pentanoic acid hydrobromide

-   4) 2-(RS)-amino-5-(4-phenoxyphenoxy)pentanoic acid hydrobromide

-   5) 2-(RS)-amino-7-(4-benzylphenoxy)heptanoic acid hydrobromide

-   6) 2-(RS)-amino-6-(4-phenylphenoxy)hexanoic acid hydrobromide

-   7) 2-(RS)-amino-6-(4-hexyloxyphenoxy)hexanoic acid hydrobromide

-   8) 2-(RS)-amino-8-(4-benzylphenoxy)octanoic acid hydrobromide

-   9) 2-(RS)-amino-6-(4-phenoxyphenoxy)hexanoic acid hydrobromide

-   10) 2-(RS)-aminomethyl-6-(4-benzylphenoxy)hexanoic acid

-   11) 1-(RS)-amino-5-(phenoxy)pentylphosphonic acid hydrobromide

-   12) 1-(RS)-amino-6-(phenoxy)hexylphosphonic acid hydrobromide

13) 1-(RS)-amino-5-(4-benzylphenoxy)pentylphosphonic acid hydrobromide

-   14) 1-(RS)-amino-4-(phenoxy)butylphosphonic acid hydrobromide

-   15) 1-(RS)-amino-7-(phenoxy)heptylphosphonic acid hydrobromide

-   16) 2-(RS)-amino-6-(4-cyclohexylmethylphenoxy)hexanoic acid    hydrobromide

-   17) 3-(RS)-amino-7-(4-benzylphenoxy)heptanoic acid

-   18) 2-(RS)-amino-2-methyl-6-(4-benzylphenoxy)hexanoic acid    hydrobromide

-   19) 1-(RS)-aminotridecanylphosphonic acid hydrobromide

-   20) 3-(RS)-amino-5-(4-benzylphenoxy)pentanoic acid

-   21) 3-(RS)-amino-6-(4-benzylphenoxy)hexanoic acid

The compounds of formula (I) or (II) as defined above with Xrepresenting NH₂ and R⁷ different from a hydrogen atom constituteprodrugs.

The compounds of formula (I) or (II) as defined above with Xrepresenting

R⁷ being a hydrogen atom constitute prodrugs.

The compounds of formula (I) or (II) as defined above with Xrepresenting

and R⁷ different from a hydrogen atom constitute prodrugs.

The compounds of formula (I) or (V) as defined above with X representingNH₂ and R⁸ and R⁹ different from a hydrogen atom constitute prodrugs.

The compounds of formula (I) or (V) as defined above where X is NH₂, R⁸is hydrogen and R⁹ is different from a hydrogen atom constituteprodrugs.

The compounds of formula (I) or (V) as defined above where X is

and R⁸ and R⁹ are different from a hydrogen atom constitute prodrugs.

The compounds of formula (I) or (V) as defined above where X is

and R⁸ and R⁹ are hydrogen constitute prodrugs.

The compounds of formula (I) or (V) as defined above where X is

and R⁸ is hydrogen and R⁹ different from a hydrogen atom constituteprodrugs.

The compounds of formula (I) or (VIII) as defined above where X is NH₂and R⁸ is different from a hydrogen atom constitute prodrugs.

The compounds of formula (I) or (VIII) as defined above where X is

and R⁸ is different from a hydrogen atom constitute prodrugs.

The compounds of formula (I) or (VIII) as defined above where X is

and R⁸ is hydrogen constitute prodrugs.

Examples of prodrugs according to the invention are:

-   22) ethyl 2-(RS)-amino-7-(4-benzylphenoxy)heptanoate hydrochloride

-   23) ethyl 2-(RS)-amino-6-(4-benzylphenoxy)hexanoate hydrochloride

-   24) diphenyl 1-amino-5-phenoxypentylphosphonate hydrobromide

-   25) ethyl-hydrogen-1-amino-5-phenoxypentylphosphonate hydrobromide

The compounds of the present invention may be prepared from easilyavailable raw materials according to one of the methods indicated below.

The reaction schemes given below describe methods which maybe used forthe preparation of the compounds of formula (I), indicating the startingmaterials, the intermediates as well as the synthesis conditions.

The abbreviations used in the present description correspond to thedefinitions below:

Ac acetyl Bn benzyl DIAD diisopropyl azodicarboxylate DMFdimethylformamide DPPA diphenylphosphoryl azide Et ethyl EtOH ethylalcohol Et₂O ethyl ether Me methyl NBu₄F tetrabutylammonium fluoridePd/C palladium on carbon Ph phenyl THF tetrahydrofuran PCC pyridiniumchlorochromate

Schemes 1 to 5 describe the preparation of substituted amino acids.

-   a) SOCl₂, EtOH, reflux-   b) NEt₃, Et₂O, CHCl₃-   c) Me₃SiCl, NEt₃-   d) MeOH-   e) Et₃N/(Ph)₃CCl-   f) NBu₄F 1M/THF-   g) PPh₃, DEAD or DIAD, R¹OH-   h) HCO₂H; NaHCO₃-   i) NaOH N; HCl 2N.

The serine is esterified in the presence of thionyl chloride and EtOH.The amino ester hydrochloride 1 obtained is treated with triethylamineand then with trimethylsilyl chloride in the presence of NEt₃ to givethe compound 2. The amino functional group is deprotected usinganhydrous MeOH and then reprotected by reacting with trityl chloride.The hydroxyl functional group is then released using tetrabutylammoniumfluoride to give the compound 3. The hydroxyl functional group of thecompound 3 is substituted according to a Mitsunobu-type reaction with aphenolic derivative of formula R¹OH to give the compound 4. Thecompounds 5 are obtained by deprotection with formic acid followed by atreatment using sodium hydrogen carbonate. The amino acid hydrochloride6 is obtained by saponification in NaOH of the compound 5 followed byacidification in 2N HCl.

The amino acid derivatives 13 and 15 are prepared from the malonates 10which are obtained either from commercial halides, or from halides 9.

Scheme 2 describes the preparation of noncommercial halides 9.

-   W=Cl, Br-   Y=O, S-   n₂ and R¹ are as described in formula (I)-   a) NaOH 9N, THF reflux-   b) K₂CO₃, DMF, room temperature

The compounds 9 may be obtained according to two routes:

By treatment in 9N sodium hydroxide under reflux in the presence of THFor by the use of powdered K₂CO₃ in the DMF at room temperature.

Scheme 3 describes the synthesis of salts of amino esters 13 and ofamino acids 15.

-   R³, n₂, Y and R¹ are as defined in formula (I).-   a) KOH, EtOH, 0° C.-   b) DPPA, NEt₃, toluene, benzyl alcohol, 80° C.-   c) H₂, Pd/C, EtOH-   d) HCl 3N-   e) NaOH, MeOH; HCl N-   f) HBr/CH₃CO₂H

The malonates of formula 10 are obtained by alkylation of a malonatewith the corresponding brominated or chlorinated derivatives 9 in thepresence of sodium ethoxide in ethanol under reflux. Monosaponificationusing a solution of KOH in EtOH gives compounds 11 which are subjectedto a Curtius reaction in the presence of DPPA, NEt₃ and benzyl alcoholin toluene at 80° C. overnight.

The benzyloxycarbonyl functional group is deprotected by catalytichydrogenation in ethanol using Pd/C to give the amino esters 13.Saponification of the compounds 12 using a solution of NaOH in MeOHgives the derivatives 14 which are subjected to the action of HBr inacetic acid to give the amino acids 15.

The amino acid derivatives 18 and 19 are prepared from the malonates 10(with R³=H) described in scheme 3.

Scheme 4 describes the synthesis of the amino ester salts 19 and of theamino acids 18.

-   a) NaOH 6N, reflux-   b) paraformaldehyde, HNEt₂ ACOEt-   c) NH₂OH HCl, NaOEt/EtOH-   d) SOCl₁, R⁷OH

The acrylic acids 17 are prepared via the diacids 16 obtained bysaponification in 6N sodium hydroxide under reflux, and then a Mannichreaction in the presence of paraformaldehyde, diethylamine in ethylacetate under reflux.

The derivatives 18 are obtained by addition of hydroxylamine in thepresence of sodium ethoxide on the acrylic acids 17 under reflux. Theamino ester salts 19 are prepared from the derivatives 18 by reaction inthe presence of thionyl chloride in an alcohol R⁷OH.

Scheme 5 shows the preparation of β-amino acids 24 and of amino acidsalts 25 from malonates.

-   a) NaOH 6N, reflux-   b) decarboxylation by heating-   c) LiAlH₄, Et₂O-   d) PCC, CH₂Cl₂

-   f) NaOH N, MeOH-   g) NH₂OH HCl, NaOEt/EtOH, reflux-   h) SOCl₂, R⁷OH.

The malonates of formula 20 are obtained by alkylation of a malonatewith the corresponding brominated or chlorinated derivatives in thepresence of sodium ethoxide in ethanol under reflux. The acids 21 areprepared via the diacids obtained by saponification in 6N sodiumhydroxide under reflux, and then a heat decarboxylation. After reductionusing lithium aluminum hydride followed by oxidation with pyridiniumchlorochromate (PCC), the aldehyde 22 is obtained. The amino acids 24are prepared via a Wittig Horner reaction using triethylphosphonoacetatefollowed by saponification in the presence of normal sodium hydroxideand then the addition of hydroxylamine in the presence of sodiumethoxide onto the acrylic derivatives.

The amino ester salts 25 are prepared from the derivatives 24 byreaction in the presence of thionyl chloride in an alcohol R⁷OH.

Schemes 6 and 7 describe the preparation of the aminophosphonicderivatives 28.

The aminophosphonic derivatives 28 are obtained according to two routes:

-   -   Route A (Scheme 6)

-   a) CH₃COCl, −5° C., 10 minutes    -   0° C., 1 hour    -   room temperature, 5 hours-   b) HBr 30%/CH₃CO₂H, 24 hours

The phosphite 26 reacts with benzyl carbamate and the aldehydes 22 togive the phosphonates 27. Deprotection using 30% HBr in acetic acidmakes it possible to obtain the derivatives 28.

-   -   Route B (Scheme 7):

-   a) NaH, DMF-   b) LiOH N, MeOH-   c) DPPA, NEt₃, toluene, benzyl alcohol, 80° C.-   d) HBr 30%/CH₃CO₂H, 24 hours

The phosphonoacetates 29 are alkylated with the halogenated derivatives9 using NaH in DMF. After saponification and Curtius reaction, thephosphonates 27 are obtained. Deprotection using 30% HBr in acetic acidmakes it possible to obtain the derivatives 28.

Scheme 8 describes the preparation of the aminophosphonic derivatives 31and 33.

-   a) HBr, CH₃COOH, 1 hour-   b) NaOH 2N, NBu₄Br-   c) HBr 30%/CH₃COOH, 1 hour.

The compound 27 is subjected to the action of a 30% HBr solution inacetic acid to give the product 31.

The compound 33 is obtained in two stages from the derivatives 27:monosaponification in the presence of a phase transfer agent in 2N NaOHand then deprotection with 30% HBr in acetic acid.

The inventors have shown that the compounds (I) according to theinvention and in particular the compounds corresponding moreparticularly to one of the formulae (II) to (VIII), have LTA₄ hydrolaseinhibiting properties.

They possess an advantageous therapeutic activity, in particular in thefield of anti-inflammatory treatments.

They also possess an advantageous antiarthritic activity.

The compounds of the invention also have antipsoriatic properties.

Moreover, the inventors have shown that the compounds of the inventionprevent the increase in the tissue levels of LTB₄ which is induced bycyclooxygenase inhibitors.

They are thus useful for the prevention of certain paradoxicalpro-inflammatory side effects of cyclooxygenase inhibitors.

Finally, LTB₄ being the endogenous ligand for the receptor inducingproliferation of the peroxisomes, the compounds of the invention alsofind applications in the fields of hepatoprotection and antimitoticaction.

The subject of the present invention is thus also the use of thecompounds of formula (I) and in particular the compounds correspondingmore particularly to one of the formulae (II) to (VIII), as medicamentswhich act as inhibitors of the activity of LTA₄ hydrolase, in particularfor an anti-inflammatory or antiarthritic treatment.

Its subject is also the use of the compounds of the invention asantipsoriatic medicaments.

Its subject is also their use as hepatoprotective or antimitoticmedicaments.

Its subject is also the use of such compounds as medicaments intendedfor the treatment of an overproduction of LTB₄, induced in particular bycyclooxygenase inhibitors.

Its subject is also the use of such compounds (I) and in particular thecompounds corresponding more particularly to one of the formulae (II) to(VIII), for the preparation of medicaments intended for inhibiting theactivity of LTA₄ hydrolase.

Its subject is in particular their use for the preparation ofmedicaments intended or the abovementioned treatments.

The compounds of formula (I) and in particular the compoundscorresponding more particularly to one of the formulae (II) to (VIII),may be administered in a physiologically acceptable vehicle orexcipient.

Accordingly, the subject of the present invention is also pharmaceuticalcompositions comprising a therapeutically effective quantity of at leastone compound of formula (I) in combination with a physiologicallyacceptable vehicle or excipient.

The compounds (I) and in particular the compounds corresponding moreparticularly to one of the formulae (II) to (VIII), of the invention mayalso be used in combination with cyclooxygenase inhibitors.

The invention thus relates to medicaments or pharmaceutical compositionscontaining a therapeutically effective quantity of a compound (I) and inparticular the compounds corresponding more particularly to one of theformulae (II) to (VIII), and a therapeutically effective quantity of acyclooxygenase inhibiting compound, optionally in combination with aphysiologically acceptable vehicle or excipient.

Examples of cyclooxygenase inhibitors useful according to the inventionare aspirin (acetylsalicylic acid), ibuprofen and diclofenac.

The medicaments or pharmaceutical compositions according to theinvention may be advantageously administered by the local cutaneous orocular routes, by the parenteral route or by the oral route, the latterbeing preferred.

The subject of the invention is also a method of treatment forinhibiting the activity of LTA₄ hydrolase in humans.

Its subject is also such a method for the treatments indicated above.

Its subject is also a method of treating an overproduction of LTB₄, inparticular induced by cyclooxygenase inhibitors.

Other advantages and characteristics of the present invention willemerge on reading the examples of preparation of compounds of formula(I) given by way of nonlimiting illustration, as well as the biologicalresults given below.

EXAMPLES

A summary table of the examples of compounds of formula (I) is givenbelow:

Summary Table Ex X n₁ R² R³ n₂ Y R¹ n₃ Z 5 —NH₂ 0 H H 0 —O——C₆H₄—(4-CH₂Ph) 0 —COOH 51 —NH₂ 0 H H 3 —O— —C₆H₄—(4-CH₂Ph) 0 —COOH 52—NH₂ 0 H H 2 —O— —C₆H₄—(4-CH₂Ph) 0 —COOH 53 —NH₂ 0 H H 2 —O——C₆H₄—(4-OPh) 0 —COOH 54 —NH₂ 0 H H 4 —O— —C₆H₄—(4-CH₂Ph) 0 —COOH 55—NH₂ 0 H H 3 —O— —C₆H₄—(4-Ph) 0 —COOH 56 —NH₂ 0 H H 3 —O——C₆H₄—(4-O(CH₂)₅CH₃) 0 —COOH 57 —NH₂ 0 H H 5 —O— —C₆H₄—(4-CH₂Ph) 0 —COOH58 —NH₂ 0 H H 3 —O— —C₆H₄—(4-OPh) 0 —COOH 61 —NH₂ 1 H H 3 —O——C₆H₄—(4-Ph) 0 —COOH 67 —NH₂ 0 H H 3 —O— —Ph 0 —PO(OH)₂ 80 —NH₂ 0 H H 4—O— —Ph 0 —PO(OH)₂ 81 —NH₂ 0 H H 3 —O— —C₆H₄—(4-CH₂Ph) 0 —PO(OH)₂ 82—NH₂ 0 H H 2 —O— —Ph 0 —PO(OH)₂ 83 —NH₂ 0 H H 5 —O— —Ph 0 —PO(OH)₂ 85—NH₂ 0 H H 3 —O—

0 —COOH 91 —NH₂ 0 H H 3 —O— —C₆H₄—(4-CH₂Ph) 1 —COOH 93 —NH₂ 0 H CH₃ 3—O— —C₆H₄—(4-CH₂Ph) 0 —COOH 100 —NH₂ 0 H H 9 —CH₂— CH₃ 0 —PO(OH)₂ 42—NH₂ 0 H H 4 —O— —C₆H₄—(4-CH₂Ph) 0 —COOEt 94 —NH₂ 0 H H 3 —O——C₆H₄—(4-CH₂Ph) 0 —COOEt 96 —NH₂ 0 H H 3 —O— —Ph 0 —PO(OPh)₂ 98 —NH₂ 0 HH 3 —O— —Ph 0 —PO(OH)(OEt) 105 —NH₂ 0 H H 1 —O— —C₆H₄—(4-CH₂Ph) 1 —COOH114 —NH₂ 0 H H 2 —O— —C₆H₄—(4-CH₂Ph) 1 —COOH

Example 1

11.98 g (90 mmol) of ethyl serinate, in hydrochloride form, aredissolved in 155 ml of CH₂Cl₂. 22.78 g (209.68 mmol) of trimethylsilylchloride are added under an inert atmosphere.

The medium is heated under reflux for 20 minutes and then thetemperature is allowed to return to room temperature. 21.2 g (209.90mmol) of triethylamine in 60 ml of CH₂Cl₂ are then added and the mediumis heated under reflux for 45 minutes.

The medium is then cooled to 0° C. and a solution of 5.4 ml (135 mmol)of anhydrous methanol in 22 ml of CH₂Cl₂ is added.

The temperature of the medium is allowed to rise to room temperature and9.1 g (90 mmol) of NEt₃ and 25 g (90 mmol) of trityl chloride aresuccessively added and the medium is stirred overnight at roomtemperature.

The medium is concentrated under vacuum and taken up in 200 ml of Et₂O.It is washed with water (once 30 ml).

The medium is dried over MgSO₄, filtered and concentrated under vacuum.

38.8 g of the desired compound are obtained.

Example 2

50 ml of a molar solution of tetrabutylammonium fluoride (NBu₄F) in THFare added, at room temperature, to a solution of 38.8 g of the productof Example 1 in 53 ml of THF. The medium is stirred for 10 minutes atroom temperature.

500 ml of Et₂O are then added and the organic phase is successivelywashed with a saturated aqueous sodium hydrogen carbonate solution(twice 60 ml) and then a saturated aqueous sodium thiosulfate solution(twice 60 ml). The organic phase is dried over MgSO₄, filtered andconcentrated under vacuum. The oily residue obtained is purified byflash chromatography using the petroleum ether/Et₂O (1/1) mixture andthen Et₂O as eluents.

29.31 g (78 mmol) of the desired compound are obtained.

Example 3

4.8 g (1.07 equivalents) of triphenylphosphine and 4.65 g (1.46equivalents) of 4-phenylphenol are successively added to a solution of6.5 g (17.2 mmol) of amino ester of Example 2 in 200 ml of toluene. Thereaction medium is vigorously stirred for 5 minutes, and then 3.70 g(1.07 equivalents) of diisopropyl azodicarboxylate are added.

The reaction medium is stirred overnight at room temperature, filteredand evaporated to dryness. The oily residue is purified by flashchromatography using the ether-petroleum ether (5/95) mixture as eluent.6.6 g (12.15 mmol) of the desired compound are thus obtained.

Example 4

6.6 g (12.15 mmol) of amino ester of Example 3 are vigorously stirredfor 5 hours at room temperature in the presence of 85 ml of formic acid.The reaction medium is then evaporated to dryness, and a white solid isobtained which is taken up in 100 ml of water. The aqueous phase iswashed with Et₂O (3 times 20 ml) and is then basified using sodiumhydrogen carbonate. The basic aqueous phase is then extracted with ethylacetate (3 times 20 ml). The organic phase is dried over MgSO₄, filteredand concentrated under vacuum. 1.86 g (6.6 mmol) of the desired compoundare obtained.

Example 5

1.86 (6.2 mmol) of product of Example 4 are mixed with 6.5 ml of N NaOHand the medium is stirred overnight at room temperature.

The aqueous phase is washed with ethyl ether (once 10 ml) and thenconcentrated under vacuum. 15 ml of HCl N are then added. The whitesolid obtained is filtered, washed with water and dried under vacuumover P₂O₅.

1.26 g (3.75 mmol) of amino acid hydrochloride are obtained.(Melting=225° C.).

The ¹H NMR is in agreement with the chemical structure.

Example 6 (Method a)

17.41 g (185.25 mmol) of phenol, 14.5 ml of THF and 62 ml of 9N NaOH areintroduced into a round-bottomed flask.

40 g (185.25 mmol) of 1,4-dibromobutane are added dropwise.

The medium is heated under reflux for 45 minutes. organic phase iswashed with 30 ml of water, dried over MgSO₄, filtered and concentrated.The oily residue is distilled under vacuum produced by a slide vanerotary vacuum pump. The fraction distilling at 80–105° C. is recoveredunder 1 mm of Hg.

15.96 g (37%) of a colorless oil are obtained.

Example 7 (Method b)

11 g (60 mmol) of 4-hydroxydiphenylmethane, 64.8 g (300 mmol) of1,4-dibromobutane, 41.5 g (300 mmol) of powdered K₂CO₃ and 94 ml ofanhydrous DMF are successively introduced into an Erlenmeyer flask.

The medium is stirred overnight at room temperature. It is filtered andthe filtrate is taken up in 300 ml of ethyl acetate. The organic phaseis washed with a saturated aqueous NaCl solution (3 times 100 ml), driedover MgSO₄, filtered and concentrated.

The excess 1,4-dibromobutane is distilled off under vacuum. 18 g (56.5mmol) of oily residue corresponding to the desired product are obtained.

Examples 8 to 17 are prepared according to one of the methods (a or b)described above.

Ex. No. Starting material Method Final product 8

b

9

b

10

b

11

b

12

b

13

b

14

b

15

b

16

a

17

a

Example 18

A sodium ethoxide solution prepared from 1.27 g (55.21 mmol) of sodiumin 32 ml of EtOH is added to a mixture of 14.3 g (89.37 mmol) of diethylmalonate and 6.78 g (21.27 mmol) of the brominated derivative of Example7. The medium is heated under reflux for 4 hours.

The medium is concentrated under vacuum, and the residue is taken up inwater and extracted with Et₂O.

The ethereal phase is washed 3 times with water, dried over MgSO₄,filtered and then concentrated. The excess diethyl malonate is removedby vacuum distillation.

6.4 g (yield 76%) of yellow oil are obtained.

Examples 19 to 25 are prepared according to the same procedure as thatdescribed in Example 18.

Ex. No. W—(CH₂)_(n2)—O—Ar product 19 ex 8 

20 ex 11

21 ex 9 

22 ex 13

23 ex 14

24 ex 10

25 ex 12

Example 26

A solution of 1.09 g (16.51 mmol) of potassium hydroxide in 16 ml ofEtOH is added at 0° C. to a solution of 6.4 g (16.08 mmol) of diester ofExample 18 in 3 ml of EtOH.

The medium is stirred overnight at 0° C.

The medium is then concentrated. The residue is taken up in 100 ml ofwater and washed with Et₂O (twice 30 ml). The aqueous phase is cooledand then acidified with a concentrated hydrochloric acid solution. Theaqueous phase is extracted with ether (twice 40 ml). The ethereal phasesare combined, dried over MgSO₄, filtered and concentrated. 4.71 g (79%)of a very viscous yellow oil are thus obtained.

Examples 27 to 33 are prepared according to the same method as thatdescribed in Example 26.

Ex. No. starting diester product 27 19

28 20

29 21

30 22

31 23

32 24

33 25

Example 34

3.67 g (13.33 mmol) of DPPA are added dropwise, followed by 1.34 g(13.33 mmol) of NEt₃ to a solution of 4.71 g of the monoacid of Example26 in 20 ml of toluene. The medium is heated at 80° C. for 1 hour. Themedium is allowed to return to room temperature and 1.65 g (15.27 mmol)of benzyl alcohol are added and the medium is heated at 80° C.overnight. The toluene phase is successively washed with water (once 10ml), with a saturated aqueous sodium hydrogen carbonate solution (once10 ml) and with water (once 5 ml). The organic phase is dried overMgSO₄, filtered and concentrated under vacuum.

6.5 g of crude product are thus obtained. The latter is purified byflash chromatography on silica with the ethyl ether-petroleum ether(3/7) mixture as eluent. 4.55 g (9.55 mmol; yield=75%) of carbamate(colorless oil) are obtained.

Examples 35 to 41 are prepared according to the same method as thatdescribed for Example 34.

Ex. No. Starting monoacid product 35 27

36 28

37 29

38 30

39 31

40 32

41 33

Example 42

1 g (2.04 mmol) of the carbamate of Example 37 is dissolved in 20 ml ofEtOH. 100 mg of 10% Pd/C are then added and then the medium ishydrogenated at a pressure of about 1 bar overnight at room temperature.

The suspension is filtered on celite and then evaporated to dryness. Theoily residue is taken up in a concentrated aqueous HCl solution. Theacidic aqueous phase is washed with Et₂O (twice 20 ml). The aqueousphase is evaporated to dryness and the residue is dried under vacuumover P₂O₅ to a constant mass. 0.64 g (yield 80%) of a white solid isthus obtained. The ¹H NMR is in agreement with the chemical structure.

Example 43

11.5 ml of an N NaOH solution are added to a solution of 4.55 g (9.55mmol) of the ester of Example 34 in 20 ml of MeOH. The medium is keptstirred overnight.

The MeOH is evaporated off under vacuum and then the residual aqueousphase is washed with ethyl ether (twice 15 ml).

The basic aqueous phase is cooled to about 5° C., is acidified to pH=1with a N HCl solution and is extracted with ethyl ether (twice 20 ml).After drying over MgSO₄, filtration and concentration under vacuum, 3.33g (78%) of a white solid are obtained.

Examples 44 to 50 are prepared according to the same procedure as thatdescribed for Example 43.

  Ex. No.

  product 44 35

45 36

46 37

47 38

48 39

49 40

50 41

Example 51

0.89 g (1.99 mmol) of the carbamate of Example 43 and 5 ml of asaturated gaseous HBr solution in acetic acid are introduced into around-bottomed flask. The stirring is maintained for 2 hours.

The acetic acid is evaporated off under vacuum and the oily residue istriturated in anhydrous ethyl ether. The medium is filtered and washedwith ethyl ether. The white solid is dried under vacuum over P₂O₅. 0.52g (66%) of the desired amino acid is obtained (melting>200° C.).

The ¹H NMR is in agreement with the chemical structure.

Examples 52 to 58 are prepared according to the same procedure as thatdescribed in Example 51.

  Ex. No.

  Product  Melting° C. 52 44

199 53 45

162 54 46

100 55 47

185 56 48

135 57 49

120 58 50

130

Example 59

9.25 g (23.24 mmol) of the malonic diester of Example 18 are dilutedwith 10 ml of water. 2.32 g (58.00 mmol) of sodium hydroxide pellets areadded.

The medium is stirred and heated under reflux for 1 h 30 min.

It is diluted with water and washed with Et₂O (once 15 ml).

The aqueous phase is cooled and acidified with a concentrated aqueoushydrochloric acid solution to pH=1. The medium is extracted with Et₂O(twice 25 ml). The ethereal phases are combined, dried over MgSO₄,filtered and concentrated. 7.92 g (100%) of a white solid are obtained.

Example 60

1.69 g (23.15 mmol) of diethylamine and then 1.04 g (30.40 mmol) ofparaformaldehyde are added to a solution of 7.92 g (23.15 mmol) of themalonic diacid of Example 59 in 50 ml of AcOEt. The medium is heatedunder reflux for 30 minutes.

The solution is then cooled using an ice and water bath, diluted with 10ml of water and then acidified with a 3N HCl solution to pH=1. Theaqueous phase is removed. The organic phase is washed with water (once10 ml), dried over MgSO₄, filtered and concentrated.

6.04 g (84%) of a white solid are obtained.

Example 61

A solution of 0.44 g (19.13 mmol) of sodium in 15 ml of anhydrous EtOHis heated under reflux. 1.35 g (19.42 mmol) of hydroxylaminehydrochloride in 1 ml of hot water are added to this solution. Themedium is cooled on ice to 5° C., filtered and the precipitate is washedwith 2 ml of anhydrous EtOH.

3 g (9.70 mmol) of acrylic acid of Example 60 are added to the filtrate.The medium is stirred and heated under reflux for 24 hours.

The medium is filtered, washed with water, with EtOH and then with ethylether. 0.71 g of a white solid (22%) (melting>200° C.) is obtained. The¹H NMR is in agreement with the chemical structure.

Example 62

The chlorinated derivative of Example 15 reacts with diethyl malonateaccording to the same method as that described in Example 18. Themalonate thus obtained is saponified according to the same procedure asthat described in Example 59 to give the desired compound.

Example 63

The diacid of Example 62 is decarboxylated by heating to 140° C. untilthe gaseous emission disappears to give the desired acid.

Example 64

A solution of 31.34 g (161.36 mmol) of acid of Example 63 in 138 ml ofanhydrous Et₂O is added to a suspension of 7.35 g (193.67 mmol) ofLiAlH₄ in 210 ml of anhydrous Et₂O. The medium is stirred overnight atroom temperature.

It is cooled on ice to 5° C. and 5.25 ml of water, 5.25 ml of 15% NaOHand 15.75 ml of water are added successively. After stirring for 2hours, the medium is filtered, rinsed with ethyl ether and the filtrateis concentrated.

19.97 g (68%) of alcohol are obtained.

Example 65

A solution of 19.77 g (110.8 mmol) of the alcohol of Example 64dissolved in 135 ml of CH₂Cl₂ is added to a solution of 48 g (222.67mmol) of PCC in 220 ml of CH₂Cl₂ cooled to 0° C. The medium is stirredfor 3 hours at room temperature, filtered on celite, evaporated todryness and purified by flash chromatography (ethyl ether/heptane 4/6).9.94 g (55.77 mmol) of aldehyde are obtained.

Example 66

6.75 g (44.6 mmol) of benzyl carbonate, 6.5 g (44.6 mmol) of diethylphosphite and 33.5 ml of acetyl chloride are mixed. The mixture iscooled to −5° C. and 9.94 g (55.77 mmol) of aldehyde of Example 65 areadded dropwise. The mixture is stirred for one hour at 0° C. and thenovernight at room temperature.

The excess acetyl chloride is removed by evaporation under vacuum andthen the residue is taken up in 50 ml of CH₂Cl₂. The medium issuccessively washed with water (once 30 ml), with a saturated aqueoussodium bisulfite solution (twice 30 ml), with a saturated aqueous NaHCO₃solution (3 times 30 ml) and with water (once 60 ml). The organic phaseis dried over MgSO₄, filtered and concentrated. 20.19 g of a crudeproduct are obtained, which product is chromatographed on silica (eluentEt₂O).

10.93 g (54.5%) of product are thus recovered.

Example 67

1.3 g (2.4 mmol) of the phosphonate of Example 66 and 3.5 ml of a 30%gaseous HBr solution in acetic acid are introduced into a round-bottomedflask. The stirring is maintained for 24 hours.

The medium is evaporated to dryness, the oily residue is triturated inanhydrous Et₂O, water is added and the solid formed is filtered. Themedium is dried under vacuum over P₂O₅. 0.62 g (1.44 mmol) of a whitesolid is obtained.

Melting: >250° C.

The ¹H NMR is in agreement with the chemical structure.

Example 68

4.9 g (21.9 mmol) of triethylphosphonoacetate are dissolved in 21 ml ofanhydrous DMF. The medium is cooled on ice to 0° C. and 0.56 g (21.9mmol) of NaH is added in portions. The medium is stirred for 15 minutesat 0° C.

A solution of 5.33 g (21.9 mmol) of brominated derivative of Example 16in 13 ml of anhydrous DMF is added. The medium is stirred overnight atroom temperature.

The medium is diluted with Et₂O, washed with water, the organic phase isdried over MgSO₄, filtered and concentrated. 6.9 g of an oily residueare obtained, which residue is purified by chromatography on silica(eluent Et₂O).

5.33 g (63%) of oil are obtained.

Examples 69 to 71 are obtained according to the same procedure as thatdescribed for Example 68.

Ex. No. W—(CH₂)_(n2)—Y—Ar product 69 ex 7 

70 ex 15

71 ex 17

Example 72

A solution of 5.33 g (13.8 mmol) of derivative of Example 68 in 32 ml ofMeOH is stirred with 20.7 ml of M LiOH. The medium is heated for 1 hourunder reflux.

The medium is evaporated to dryness, water is added and the medium iswashed with Et₂O. The aqueous phase is acidified with an N HCl solutionand it is extracted with Et₂O. The ethereal phases are combined, driedover MgSO₄, filtered and concentrated. 3.93 g (79%) of the desired acidare obtained.

Examples 73 to 75 are obtained according to the same procedure as thatdescribed for Example 72.

Ex. No. starting ester product 73 ex 69

74 ex 70

75 ex 71

Example 76

The acid of Example 72 is converted to carbamate 76 according to thesame procedure as that described in Example 34.

Examples 77 to 79 are obtained according to the same procedure as thatdescribed in Example 34.

Ex. No. starting ester product 77 ex 73

78 ex 74

79 ex 75

Example 80

The phosphonate of Example 76 is converted to an aminophosphonicderivative according to the same procedure as that described in Example67 (melting>250° C.).

The ¹H NMR is in agreement with the chemical structure.

Examples 81 to 83 are obtained according to the same procedure as thatdescribed in Example 67.

Ex. No. starting phosphonate product melting (° C.) 81 77

  180 82 78

>250 83 79

>250

Example 84

The compound of Example 84 is prepared from 1,4-dibromobutane and4-(cyclohexylmethyl)phenol (Helv. Chem. Acta. Vol 77, (1994), 1241 and1255) according to the same procedure as that described for Example 7(method b).

Example 85

The product of Example 85 is prepared according to the same reactionsequence as that used for the synthesis of Example 51.

Melting: 121° C.

Example 86

The diester of Example 19 is saponified according to the same procedureas that described in Example 59.

Example 87

The diacid of Example 86 is decarboxylated at 130° C. for 30 minutes.

A solution of 10.27 g (36.1 mmol) of the acid obtained afterdecarboxylation in 30 ml of anhydrous Et₂O is added to a suspension of1.64 g (1.2 equivalents) of LiAlH₄ in 47 ml of anhydrous Et₂O. Themedium is stirred overnight at room temperature.

After hydrolysis and filtration, 7.68 g (28.4 mmol) of the desiredalcohol are obtained.

Example 88

7.68 g (28.4 mmol) of the preceding alcohol dissolved in 35 ml of CH₂Cl₂are added at 0° C. to 12.25 g (2 equivalents) of pyridiniumchlorochromate dissolved in 56 ml of CH₂Cl₂. After 3 hours at roomtemperature, the medium is filtered on silica and purified by flashchromatography (eluent 7/3 heptane/Et₂O).

4.63 g (17.25 mmol) of aldehyde are obtained.

Example 89

523 mg (1.2 equivalents) of NaH are added at 0° C. to a solution of 3.77g (1.2 equivalents) of trimethylphosphonoacetate in 52 ml of anhydrousTHF. The medium is stirred for 15 minutes at 0° C. and then a solutionof 4.63 g (17.25 mmol) of aldehyde of Example 88 in 20 ml of anhydrousTHF is added and the medium is stirred for 4 hours at room temperature.

The medium is evaporated, water is added, the medium is extracted withEt₂O, dried with MgSO₄ and then evaporated. The medium is purified bychromatography on silica (eluent 1/9 Et₂O/heptane).

2.56 g (7.89 mmol) of the desired ester are obtained.

Example 90

16 ml of N NaOH are added to 2.56 g (7.9 mmol) of the preceding esterdissolved in 26 ml of MeOH. The medium is heated for one hour underreflux, acidified with N HCl, extracted with Et₂O, dried over MgSO₄,filtered and concentrated.

2.36 g (7.6 mmol) of the desired acrylic acid are obtained.

Example 91

The preceding acid is treated according to the same procedure as thatdescribed in Example 61.

Melting: 205° C.

The ¹H NMR is in agreement with the chemical structure.

Example 92

Diethyl methyl malonate is alkylated with the brominated derivative ofExample 7 according to the same procedure as that described in Example18.

Example 93

The product of Example 92 is treated according to the same reactionsequence as that used for the synthesis of Example 51.

Melting: 196° C.

Example 94

The carbamate of Example 38 is hydrogenated according to the sameprocedure as that described for Example 42 to lead to Example 94.

Melting>250° C.

Example 95

The same procedure is used as that described in Example 66 except thatthe diethyl phosphite is replaced with diphenyl phosphite.

Example 96

The product of the preceding example, 0.5 g (1 mmol), is stirred in 2 mlHBr/CH₃COOH at 30% for 2 hours.

The medium is evaporated to dryness and triturated in dry Et₂O untilprecipitation of the salt occurs.

0.4 g of the desired product is obtained after filtration and drying.

The ¹H NMR is in agreement with the chemical structure.

Example 97

0.3 g of NBu₄Br and 8 ml of 2N NaOH are added to 1 g (2.22 mmol) ofproduct of Example 66. The medium is stirred for 2 days at roomtemperature.

The medium is diluted with water and washed with Et₂O. The aqueous phaseis acidified with N HCl and then concentrated H₂SO₄. The medium isextracted with Et₂O, dried over MgSO₄ and evaporated. 0.41 g of thedesired product is obtained.

Example 98

The product of Example 97 is deprotected according to the same procedureas that described in Example 96.

Example 99

The same procedure is used as that described in Example 66 except thatthe aldehyde of Example 65 is replaced with tridecanal.

Example 100

The product of Example 99 is deprotected according to the same procedureas that described in Example 67.

Melting: 252° C.

The ¹H NMR is in agreement with the chemical structure.

Example 101

4.4 g (31.67 mmol) of 3-bromo-1-propanol, 4.9 g (26.5 mmol) of4-hydroxydiphenylmethane, 11 g (79.59 mmol) of powdered K₂CO₃ and 45 mlof anhydrous DMF are successively introduced into an Erlenmeyer flask.

The medium is stirred overnight at room temperature.

The medium is filtered and the filtrate is taken up in 30 ml of ethylacetate. The organic phase is washed with water (twice 10 ml) and thenwith a saturated aqueous NaCl solution (once 10 ml), dried over MgSO₄,filtered and concentrated.

The residue is purified by flash chromatography on silica with the ethylether/heptane (50/50) mixture. 5.35 g (22.07 mmol) of the expectedproduct are obtained.

Example 102

The alcohol of Example 101 is oxidized according to the same procedureas that described in Example 88.

Example 103

2.97 g (1.1 equivalents) of trimethylphosphonoacetate and 0.69 g (1.1equivalents) of lithium hydroxide are successively added to a solutionof 3.56 g (14.8 mmol) of aldehyde of Example 102 in 15 ml of anhydrousTHF. The medium is stirred overnight at room temperature under argon.100 ml of ethyl ether are added and the organic phase is washed withwater (twice 10 ml) and with a saturated aqueous NaCl solution (once 10ml). The organic phase is dried over molecular sieve, filtered andconcentrated. The medium is purified by chromatography on silica(eluent, Et₂O/heptane 1/9). 2.27 g (7.66 mmol) of the desired ester areobtained.

Example 104

The ester of Example 103 is saponified according to the same procedureas that described in Example 90.

Example 105

The preceding acid is treated according to the same procedure as thatdescribed in Example 61.

Melting: 240° C.

The ¹H NMR is in agreement with the chemical structure.

Example 106

10 g (54.28 mmol) of 4-hydroxydiphenylmethane, 1.86 g (0.1 equivalent)of nBu₄NB_(r)7.2 g (1.5 equivalents) of ethylene carbonate and 100 ml ofanhydrous DMF are successively added to a three-necked round-bottomedflask. The medium is heated at 140° C. under argon for 4 hours. It isallowed to return to room temperature, 100 ml of ethyl ether are addedand the organic phase is washed with water (3 times 40 ml) and then witha saturated aqueous NaCl solution (once 20 ml). The organic phase isdried over molecular sieve, filtered and concentrated. The residue ispurified by flash chromatography on silica with an ethyl ether/heptane(50/50) mixture.

6.4 g of the expected product are obtained.

Example 107

2.14 g (1.2 equivalents) of SOCl₂ and then 76 mg (1.1 mmol) of imidazoleare added, at a temperature of about +5° C., to 3.41 g (15 mmol) ofalcohol of Example 106. The medium is stirred for 15 minutes at roomtemperature and then for 4 hours at 100° C. The medium is then allowedto return to room temperature, 20 ml of water are added and the aqueousphase is neutralized with NaHCO₃ and extracted with ethyl ether (twice20 ml). The organic phase is dried over molecular sieve, filtered andconcentrated. 3.45 g (13.98 mmol) of the expected chlorinated derivativeare obtained.

Example 108

The diester of Example 108 is prepared according to the same procedureas that described in Example 18, but starting with the chlorinatedderivative 107.

Example 109

The diester of Example 108 is saponified according to the same procedureas that described in Example 59.

Example 110

The diacid of Example 109 is decarboxylated and reduced according to thesame procedure as that described in Example 87.

Example 111

The alcohol of Example 110 is oxidized according to the same procedureas that described in Example 88.

Example 112

The aldehyde of Example 111 is converted to the ester 112 by a WittigHorner reaction according to the same procedure as that described inExample 103.

Example 113

The ester of Example 112 is saponified according to the same procedureas that described in Example 90.

Example 114

The acid 113 is treated according to the same procedure as thatdescribed in Example 61.

Melting: 226° C.

The ¹H NMR is in agreement with the chemical structure.

BIOLOGICAL ACTIVITY

Biological Trials of the Compounds According to the Invention

1) Inhibition of the Aminopeptidase Activity of Recombinant LTA₄Hydrolase

The compounds were tested using human recombinant LTA₄ hydrolase (Minamiet al., FEBS Letters, 1988, 229: 279). The LTA₄ hydrolase expressed byE. coli JM109 is purified mainly according to Minami et al., (J. Biol.Chem., 1987, 262: 13873).

The inhibition of the aminopeptidase activity of the enzyme is measuredby means of a fluorimetric method in 96-well microplates. Therecombinant enzyme (0.5 μg in 50 μl of 50 mM Tris-HCl pH 7.4) ispreincubated for 10 minutes at 37° C. in the presence of inhibitor andof dithiothreitol (DTT, 10⁻⁵ M). The substratealanyl-amido-methylcoumarin (Ala-AMC, 25 μM-Tris HCl 50 mM, pH 7.4) isadded and the incubation is continued for 15 minutes at 37° C. Therelease of AMC is measured by fluorimetry.

To evaluate the specificity of the compounds according to the invention,some of them were also tested for their capacity to inhibit the activityof membrane aminopeptidase M (EC 3.4.11.2). The same test is carried outwith 0.1 μg of aminopeptidase M (Pierce, USA).

2) Inhibition of the Biosynthesis of LTB₄ In Vitro

The biosynthesis of LTB₄ is measured in human whole blood in thepresence of inhibitors of LTA₄ hydrolase according to the invention. A50 μl blood sample collected over sodium heparinate is preincubated for10 minutes at 37° C. in the presence of inhibitor (50 mM Tris-HCl, 0.15M NaCl, 10⁻⁵ M DTT, pH 7.4).

The LTA₄ substrate was freshly prepared by alkaline hydrolysis of LTA₄methyl ester (Cayman Chemical Co., USA). After incubating for 10 minutesin the presence of LTA₄ (1 μM in 50 mM Tris-HCl, 0.15 M NaCl, 0.5% BSA,pH 7.4), the reaction is stopped by diluting 1/20 in 0.1 M potassiumphosphate buffer containing 1.5 mM NaN₂, 0.4 M NaCl, 1 mM EDTA, 0.1%BSA, pH 7.4, −4° C.

The LTB₄ is assayed by enzyme-linked immunoassay (Cayman Chemical Co.,USA).

3) Inhibition of the Biosynthesis of LTB₄ ex vivo

The compounds inhibiting LTA₄ hydrolase according to the invention aresuspended in 1.25% methyl cellulose and administered to mice by the oralroute at the dose of 10 mg/kg. Thirty minutes later, the mice aresacrificed and the blood collected over lithium heparinate. The blood isthen, as above, incubated for 10 minutes at 37° C. in the presence ofLTA₄ and then the LTB₄ formed is assayed by enzyme-linked immunoassay.

The compounds of the invention have proved active in low concentrationin vitro (for example the Ki of compound 51 was 32 nM) and in low doseby the oral route (<1 mg/kg, or even<0.1 mg/kg).

The compounds according to the invention, in particular thosecorresponding to one of the formulae (II) and (VI) allow the inhibitionof LTA₄ hydrolase in vitro and in vivo. They also make it possible toinhibit the biosynthesis of LTB₄, which makes them compounds of interestin human therapy.

The compounds according to the invention may be administered inparticular by the oral route.

They exhibit good bioavailability and low toxicity.

The compounds according to the invention, in particular the compounds ofthe aminophosphonate type, possess a long duration of action.

Accordingly, these compounds exert, over a period of more than 24 hours,complete inhibition of the blood LTA₄ hydrolase activity afteradministration by the oral route at doses of 1 to 10 mg/kg in rats.

1. A compound corresponding to the following formula (I):

in which X is NH₂ n₁ and n₃ are equal to 0 or 1, with (n₁+n₃) equal to 0or 1 n₂ varies from 0 to 10 Y is selected from the following groups: i)—O— R¹ is selected from the following groups: i) a phenyl group which isunsubstituted or which is mono- or polysubstituted with substituentsselected from halogen atoms and CF₃, lower alkyl, lower alkoxy, NH₂,NO₂, CN, OH, CO₂H, OPh, OCH₂Ph, SCH₃, SCH₂CH₃ and NHCOR⁶ groups Z is

R² and R³ are independently selected from the following groups: i) ahydrogen atom ii) a lower alkyl group iii) a lower alkyl groupsubstituted with a halogen atom iv) a CF₃ group v) a halogen atom; R⁶represents a lower alkyl group; and R⁸ and R⁹ are independently selectedfrom a hydrogen atom, a phenyl group, a lower alkyl group and a loweracetylthioalkylene group, as well as their diastereoisomers andenantiomers and their therapeutically acceptable salts.
 2. The compoundas claimed in claim 1, where R² and/or R³ represents a hydrogen atom. 3.The compound as claimed in claim 1, where R² and R³ represent a hydrogenatom.
 4. The compound as claimed in claim 1, where R² and/or R³ isdifferent from hydrogen.
 5. The compound as claimed in claim 1, where n₁or n₃ are equal to
 0. 6. The compound as claimed in claim 1, where n₁ orn₃ is different from
 0. 7. The compound as claimed in claim 1, where Zrepresents —PO(OH)₂.
 8. The compound as claimed in claim 1, where itcorresponds to the following formula (VI):

wherein Y, n₂ and R¹ have the meaning indicated in claim
 1. 9. Thecompound as claimed in claim 1, where n₂ varies from 2 to
 5. 10. Thecompound as claimed in claim 1, where n₂ is equal to
 3. 11. The compoundas claimed in claim 1, where R¹ represents an unsubstituted phenylgroup.
 12. The compound as claimed in claim 1, where R¹ represents aphenyl group which is mono- or poly-substituted with a group selectedfrom lower alkyl, lower alkoxy, OPh and OCH₂Ph, preferably OPh, groups.13. The compound as claimed in claim 1, where R¹ represents a phenylgroup which is substituted with a Ph, CH₂Ph, CH₂-cycloalkyl orCH₂-cycloalkene groups.
 14. The compound as claimed in claim 1, where R¹represents a phenyl group substituted with a Ph or CH₂ Ph group.
 15. Thecompound as claimed in claim 1, where R¹ represents a hydrogen atom or alower alkyl group.
 16. The compound as claimed in claim 1, where it isselected from: 11) 1-(RS)-amino-5-(phenoxy)pentylphosphonic acidhydrobromide 12) 1-(RS)-amino-6-(phenoxy)hexylphosphonic acidhydrobromide 13) 1-(RS)-amino-5-(4-benzylphenoxy)pentylphosphonic acidhydrobromide 14) 1-(RS)-amino-4-(phenoxy)butylphosphonic acidhydrobromide 15) 1-(RS)-amino-7-(phenoxy)heptylphosphonic acidhydrobromide.
 17. The compound as claimed in claim 1, where R⁸ and/or R⁹are independent and different from hydrogen.
 18. The compound as claimedin claim 1, where it is selected from 24) diphenyl1-amino-5-phenoxypentylphosphonate hydrobromide 25)ethyl-hydrogen-1-amino-5-phenoxypentylphosphonate hydrobromide.
 19. Apharmaceutical composition, comprising a compound of formula (I)according to claim 1, with a pharmaceutically acceptable recipient. 20.A pharmaceutical composition comprising, as active ingredient, thecompound of formula (I) as claimed in claim 1 and a cyclooxygenaseinhibitor, selected from the group consisting of aspirin, ibuprofen anddiclofenac.
 21. An antiarthritic treatment method comprisingadministering a compound of formula (I) as claimed in claim 1 to amammal.
 22. An antipsioratic treatment method comprising administering acompound of formula (I) as claimed in claim 1 to a mammal.
 23. A methodfor treating an overproduction of LTB₄, induced by cyclooxygenaseinhibitors, comprising administering a compound of formula (I) asclaimed in claim 1 to a mammal.